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September 17, 2026Genome MedicineOpen Access

Beyond BRCAness: ATM pathway defects confer sensitivity to topoisomerase I inhibition

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Authors

MKMandana KamgarTMThomas McFallMMMaahum Mehdi

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Overview

Cohort study demonstrates superior disease control with irinotecan in ATM/CHEK2-mutated pancreatic cancer, highlighting topoisomerase I inhibitors as targeted therapies.

Key Points

  • To determine whether ATM pathway alterations in pancreatic ductal adenocarcinoma create specific therapeutic vulnerabilities to topoisomerase I inhibitors over standard platinum or PARP-inhibitor regimens.
  • Analyzed clinical outcomes across 48 chemotherapy lines in 16 patients with ATM/CHEK2-mutated advanced or metastatic pancreatic ductal adenocarcinoma from an institutional database.
  • Engineered homozygous (ATM -/-) and heterozygous (ATM +/-) knockouts in PANC-1 cells via CRISPR editing to assess colony formation, proliferation, and viability following treatment with SN-38.
  • Patients receiving irinotecan-containing regimens achieved significantly longer median progression-free survival than those receiving alternative regimens, including platinum/PARP inhibitors (11.5 vs. 3 months, p < 0.001).
  • Cellular sensitivity to SN-38 correlated with the extent of ATM loss in colony formation assays (half-maximal inhibitory concentration: 0.3 nM for ATM -/-, 0.8 nM for ATM +/-, and 7.0 nM for wild-type) and proliferation assays (all p < 0.01).

Cite This Study

Kamgar et al. (2026) studied this question.

synapsesocial.com/papers/6aabb6f95f706d05830e5d38https://doi.org/10.1186/s13073-026-01774-z
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Abstract A031: Identification of therapeutic vulnerabilities in the subset of pancreatic ductal adenocarcinoma (PDAC) with homologous recombination deficiency2024
  2. 2<i>ATM</i> mutations in pancreatic cancer: A real-world analysis of molecular landscapes, clinical heterogeneity, and prognostic impact.2026
  3. 3PARP inhibitor synthetic lethality in ATM biallelic mutant cancer cell lines is associated with BRCA1/2 and RAD51 downregulation2024 · 5 citations
  4. 4Abstract 1738: Alnodesertib (ART0380) in combination with irinotecan is highly efficacious in preclinical models of ATM null pancreatic cancer2026
  5. 5Targeting ATR-CHK1 and ATM-CHK2 Axes in Pancreatic Cancer—A Comprehensive Review of Literature2026 · 2 citations